Biallelic Inactivation of the Dual Oxidase Maturation Factor 2 (DUOXA2) Gene as a Novel Cause of Congenital Hypothyroidism

Abstract

We report the first mutation in DUOXA2, identified in a patient with CH and dyshormonogenic goiter. Results of our studies provide evidence for the critical role of DUOXA2 in thyroid hormonogenesis. Biallelic DUOXA2 mutations are a novel genetic event in permanent CH.

Monoallelic thyroid peroxidase gene mutation in a patient with congenital hypothyroidism with total iodide organification defect

“…Mutations in thyroid peroxidase (TPO) are the most frequent genetic alterations in dyshormonogenesis, with prevalence of 1/40,000 newborns (3). Mutations in thyroglobulin (TG) (4), sodium iodide symporter (NIS), pendrin (PDS), dual oxidase 2 (DUOX2) (5), dual oxidase maturation factor 2 (DUOXA2) (6), and iodotyrosine deiodinase (DEHAL1) (7) genes have been also identified in patients with dyshormonogenesis.…”

“…The sequences were compared with those of the human TPO gene sequence (GeneID: 7173). In order to amplify and sequence the coding region and intron-exon borders of the DUOX2 and DUOXA2 gene we used the primers and conditions previously described (5,6). These sequences were compared with those of human DUOX2 and DUOXA2 (GeneID: 50506 and GeneID: 405753, respectively).…”

Homozygous <i>DUOXA2</i> mutation (p.Tyr138^*) in a girl with congenital hypothyroidism and her apparently unaffected brother: Case report and review of the literature

“…A vector encoding the p.Tyr138* mutation was created with the also evidenced by the facts that both biallelic DUOX2 mutations [4] and biallelic DUOXA2 mutations [5] cause congenital hypothyroidism (CH) in humans, while neither DUOX1 mutations nor DUOXA1 mutations have been identified so far. Nonetheless, DUOX1 (and possibly DUOXA1) could have a minor role in H 2 O 2 production in the thyroid, because CH in biallelic DUOX2 mutation carriers is often transient [6], and those mutation carriers produce thyroid hormones presumably via DUOX1 in the post-infantile period [7].…”

“…Nonetheless, DUOX1 (and possibly DUOXA1) could have a minor role in H 2 O 2 production in the thyroid, because CH in biallelic DUOX2 mutation carriers is often transient [6], and those mutation carriers produce thyroid hormones presumably via DUOX1 in the post-infantile period [7]. As for DUOXA2 mutation carriers, only four unrelated CH patients have been reported [5,[8][9][10], and thus the phenotypic spectrum remains to be established. Here, we report the fifth DUOXA2 mutation-carrying CH patients, whose brother also had the identical homozygous mutation but did not have CH.…”

“…In the literature, four CH patients with biallelic DUOXA2 mutations were found [5,[8][9][10], and clinical information was available in three out of the four published cases (Table 1) [5,8,10]. Blood-spot TSH levels at newborn screening ranged from 48 to 135 mU/L, and serum TSH levels at the first medical examination ranged from 12 to 151 mU/L.…”